Eicosatriynoic acid esters and amides and their application in pharmaceutical and cosmetic practice

ABSTRACT

Compound, corresponding to the formula 
     
         C.sub.8 H.sub.17 --(C.tbd.C--CH.sub.2).sub.3 --CH.sub.2 CH.sub.2 CH.sub.2 
    
      R O                                                       (I) 
     in which R is a C 1  -C 8  lower alkoxy or C 4  -C 6  cycloalkoxy group, substituted with one or more hydroxyl groups and/or interrupted by one or more hetero atoms chosen from oxygen and sulphur, an amino group of structure ##STR1## in which R 1  or R 2 , which may be identical or different, denote a hydrogen atom or a linear or branched C 1  -C 8  lower alkyl radical, optionally interrupted by one or more hetero atoms chosen from oxygen, sulphur and nitrogen, this alkyl radical being able to be substituted with one or more hydroxyl groups, R 1  and R 2  not being able to denote hydrogen simultaneously, or alternatively R 1  and R 2  form, together with the nitrogen atom, a heterocyclic system optionally containing oxygen, sulphur or nitrogen as an additional hetero atom, one of the radicals R 1  and R 2  also being able to denote, when the other is a hydrogen atom, an aryl radical of formula (II): ##STR2## or alternatively a benzyl radical of formula (III): ##STR3## in which formulae R 3  and R 4 , denote, independently of each other, a hydrogen atom, a C 1  -C 4  alkyl radical, a hydroxyl group, a halogen atom or a carboxyl or trifluoromethyl group, the amine group also being able to originate from a sugar, and also the isomers and salts thereof which are pharmaceutically and cosmetically acceptable.

The subject of the present invention is new compounds consisting ofeicosatriynoic acid esters and amides, and also their application, onthe one hand as a therapeutic agent in the treatment or prophylaxis ofallergic diseases and in the treatment of dermatoses and inflammatorydiseases, and on the other hand in cosmetic compositions.

It is known that a number of substances perform an important role in theinflammatory process of the skin, such as acne, dermatoses such as, forexample, psoriasis, eczema, and the like. These substances, includingprostaglandins, hydroxyeicosatetraenoic acids, thromboxanes andleukotrienes, all have a common origin, namely arachidonic acid (see"VOORHEES, Leukotrienes and Other Lipoxygenase Products in thePathogenesis and Therapy of Psoriasis and Other Dermatoses" ArchDermatol. Vol. 119, July 1983, 541-547).

The formation of these substances results mainly from the release ofarachidonic acid bound through an ester bond to the lipids present inthe epidermis (for example the phospholipids).

For the treatment of skin diseases, prior recommendations have alreadybeen made to use either cyclooxygenase inhibitors, which inhibitprostaglandin formation, such as indomethacin, vitamin E, and the like,or substances capable of inhibiting lipoxygenases, such aseicosatetraynoic acid.

For the treatment of psoriasis, 5,8,11,14-eicosatetraynoic acid and also5,8,11-eicosatriynoic acid, and their lower alkyl esters, have alreadybeen recommended (US-A-4,190,669).

The applicants have discovered that, surprisingly, particular esters oramides of 5,8,11-eicosatriynoic acid inhibited the enzymatic metabolismof arachidonic acid induced by cyclooxygenase and lipoxygenases. Thisresult is especially unexpected in view of the blocking of the acidicfunction in the form of the esters or amides defined below.

These compounds show, moreover, a bioavailability which is differentfrom that of the corresponding acids and which endows them with improvedtherapeutic properties.

The subject of the present invention is hence the new5,8,11-eicosatriynoic acid derivatives.

Another subject of the invention consists of the pharmaceuticalcompositions containing such compounds as an active substance.

Another subject of the invention also consists of the process forpreparing these derivatives.

The subject of the invention is also the use of these compounds in thecosmetics field, in particular in compositions for treating acne andcompositions for use before or after exposure to sunlight, or in thetreatment of seborrhoeic dermatitis.

Other subjects of the invention will emerge on reading the descriptionand the examples which follow.

The compounds according to the invention are essentially characterizedin that they correspond to the formula:

    C.sub.8 H.sub.17 (C.tbd.C--CH.sub.2).sub.3 CH.sub.2 CH.sub.2 COR (I)

in which:

R is a C₁ -C₈ lower alkoxy or C₄ -C₆ cycloalkoxy group, substitited withone or more hydroxyl groups and/or interrupted by one or more heteroatoms chosen from oxygen and sulphur, or alternatively an amino group ofstructure ##STR4## in which R₁ and R₂ may be identical or different andcorrespond to a hydrogen atom, a linear or branched C₁ -C₈ lower alkylradical, a C₁ -C₈ lower alkyl radical interrupted by one or more heteroatoms chosen from oxygen, nitrogen or sulphur and/or substituted withone or more hydroxyl groups, R₁ and R₂ do not simultaneously denote ahydrogen atom, R₁ and R₂ also being able to form, with the nitrogen atoma heterocyclic system optionally containing nitrogen, oxygen or sulphuras an additional hetero atom;

one of the radicals R₁ or R₂ can also denote, when the other is ahydrogen atom, an aryl radical of formula (II): ##STR5## or a benzylradical of formula (III): ##STR6## in which formulae R₃ and R₄ denote,independently of each other, a hydrogen atom, a C₁ -C₄ alkyl radical, ahydroxyl group, a halogen atom such as chlorine, bromine or fluorine acarboxyl group or a trifluoromethyl group,

the amino group can also originate from a sugar such as, preferably,glucosamine,

and also their isomers and the pharmaceutically and cosmeticallyacceptable salts, such as the salts of inorganic or organic acids, forexample hydrochloric, lactic, tartaric and citric acids.

The especially preferred compounds of the invention are chosen from thefollowing compounds:

when R denotes a substituted C₁ -C₈ alkoxy group, it denotes moreespecially a 2-hydroxyethoxy or 2-hydroxypropyloxy group or a2,3-dihydroxypropyloxy group or its isomer, the1,3-dihydroxy-2-propyloxy radical;

when R denotes an amino group of structure ##STR7## the preferredmeanings of R₁ and R₂ are as follows: for R₁ and/or R₂ lower alkyl,methyl, ethyl, isopropyl,

for R₁ and R₂ alkyl interrupted by one or more hetero atoms such as--CH₂ CH₂ OCH₂ CH₂ OH

for R₁ and/or R₂ C₁ -C₈ alkyl substituted with one or more hydroxylgroups, the preferred meanings are as follows:

CH₂ CH₂ OH, CH₂ CHOHCH₃, CH₂ CHOHCH₂ OH;

when R₁ and R₂ form a ring, the preferred compounds of the invention areamides of pyrrolidine, morpholine, piperazine and4-(2'-hydroxyethyl)piperazine;

when one of R₁ and R₂ denotes H and the other an aryl radical, thelatter is a para-hydroxyphenyl radical.

Among the compounds of formula I, the following may be mentioned:

2',3'-dihydroxypropyl 5,8,11-eicosatriynoate

N-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide

N-ethyl-5,8,11-eicosatriynamide

pyrrolidino-5,8,11-eicosatriynamide

N,N-bis(2-hydroxyethyl)-5,8,11-eicosatriynamide

N-(2-hydroxyethyl)-5,8,11-eicosatriynamide

N-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide

4'-(2-hydroxyethyl)piperazino-5,8,11-eicosatriynamide

N-(para-hydroxyphenyl)-5,8,11-eicosatriynamide.

Among the preferred compounds, the following may be mentioned:

N-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide

2',3'-hydroxypropyl 5,8,11-eicosatriynoate

N-ethyl-5,8,11-eicosatriynamide

pyrrolidino-5,8,11-eicosatriynamide

4'-(2-hydroxyethyl)piperazino-5,8,11-eicosatriynamide.

These esters or amides are prepared from 5,8,11-eicosatriynoic acid,which has itself been known for a long time (see A. VAN DORP et al.,Recueil 85, 1966, page 1233). The scheme A below depicts this synthesis.The synthesis of the ¹⁴ C-labelled product and also the synthesis ofmany homologs of this acid are described in particular in the thesis byULLMAN MYRON, 1970, Ohio State University, Ph.D., Biochemistry.

The acid, moreover, is described in U.S. Pat. No. A 3,033,884.

The applicants have also discovered, and this constitutes anothersubject of the invention, a new process for preparing5,8,11-eicosatriynoic acid, by means of which process the esters andamides according to the invention may be produced in more advantageousyields and at more advantageous costs (Scheme B).

This process is essentially characterized in that1-halo-2,5-tetradecadiyne (3) is synthesized in a single stage byreacting 1-decyne (1) with the 1,4-dihalo-2-butyne (2) in the presenceof a strong base such as an organomagnesium compound. During thisreaction, the acetylide of the decyne (1) is formed by exchange withthis strong base and is then reacted with the dihalide (2) in excessand, surprisingly, the compound (3) is obtained in very good yield. Theresult is especially surprising when it is known that the synthesis ofthis halide was hitherto obtained by carrying out chain-elongationreactions using a propargyl alcohol derivative, with relatively lowyields. ##STR8##

The synthesis of 5-hexynoic acid (6), which is reacted with the1-halo-2,5-tetradecadiyne (3), is known per se and consists initially inreacting potassium cyanide with the 1-halopentyne (4). The5-hexynenitrile (5) is then converted to the corresponding acid (6) bythe action of potassium hydroxide followed by acidification of thereaction medium.

The acetylide of the acid (6) is formed by reaction with two equivalentsof organomagnesium compound. The dianion is then coupled with the1-halotetradecadiyne in an ether such as tetrahydrofuran. This reactioncan optionally be performed in the presence of an aprotic solvent suchas hexamethylphosphoramide (HMPA). A good yield of 5,8,11-eicosatriynoicacid (7) is then obtained.

The esters according to the invention are obtained by reactions whichare known per se. They are prepared, in particular, according to a firstmethod by reaction of phosphorus pentachloride with the acid of formula(7), followed by the reaction of the corresponding acid chloride (8)with an alcohol (9) (R'-OH), R' is a C₁ -C₈ lower alkyl or a C₄ -C₆cycloalkyl group, substituted with one or more hydroxyl groups and/orinterrupted by one or more hetero atoms chosen from oxygen and sulphur.This reaction corresponds to the following scheme: ##STR9##

The second method uses the process described in H. NORMANT et al.,Synthesis 1975, page 805, which consists in forming the potassium saltof the acid in DMF by reaction with potassium bicarbonate in thepresence of a diamine (N,N,N',N'-tetramethyl-1,3-propylenediamine). Thepotassium carboxylate is then reacted with a halide of formula (R'--X),where R' is defined above and X denotes a halogen such as Br or Cl:##STR10##

When the first method is used and the radical R' is substituted with atleast two hydroxyl groups, such as, for example, the ester of glycerol,it is preferable to protect two of the three hydroxyl groups in the formof dioxolane (11), according to the following reaction scheme: ##STR11##

The dioxolane (11) is then reacted with the acid chloride (8). The ester(12) thereby obtained is treated under mild conditions in methanol inthe presence of an acid catalyst to remove the group protecting the twoalcohol groups, according to the following reaction scheme: ##STR12##

The amides according to the invention can be obtained by two methods.

The first method consists in reacting the acid chloride (8) with theamine ##STR13## in the presence of a tertiary amine, according to thefollowing reaction scheme: ##STR14##

The second method employs a known process described in HEINZ A. STAAB,Liebigs Ann. Chem., 1957, 609, 75. In this process, the acid (7) isreacted by DMF, brought to 80° C., with carbonyldiimidazole (CDI) for 2to 3 hours. An excess of amine of formula ##STR15## is then added atroom temperature to the intermediate formed, according to the followingreaction scheme: ##STR16## in which R₁ and R₂ have the meanings statedabove.

The compounds of formula (I) according to the invention have especiallynotable activity in respect of the inhibition of the metabolism ofarachidonic acid, particularly as regards the lipoxygenases which are atthe source of the formation of the leukotrienes and the hydroxylatedacids which perform an important role in the inflammatory process.

The compounds according to the invention can be administered to humansor animals by means of compositions containing, in addition, apharmaceutically acceptable carrier or diluent. These compositions canalso optionally contain other active substances which do not have anantagonistic effect on the compounds according to the invention.

The compounds according to the invention can be administeredsystemically or locally.

For enteral administration, the drugs can take the form of tablets,gelatin capsules, dragees, syrups, suspensions, solutions, powders,granules, emulsions and the like. For topical administration, thepharmaceutical compositions based on compounds according to theinvention take the form of ointments, tinctures, creams, salves,powders, patches, impregnated pads, solutions, lotions, gels, sprays orsuspensions.

These compounds for topical administration can take either anhydrousform or the form of an aqueous solution, according to the clinicalindication.

The compounds according to the invention can also be administeredparenterally and, in particular, intravenously, intramuscularly,intraperitoneally, subcutaneously or intradermally.

For parenteral administrations, and more especially injections, theactive substance is used in a sterile vehicle such as water. The activesubstance is either suspended or dissolved in the vehicle.

The compounds according to the invention can also be used in cosmetics,in particular in creams and skin lotions, such as in products for usebefore exposure to sunlight, soothing products for use after exposure tosunlight, antiseborrhoeic products or products for treating acne.

These medicinal and cosmetic compositions according to the invention cancontain inert additives or pharmcodynamically or cosmetically activeadditives, and in particular:

hydrating agents such as thiamorpholinone and its derivatives or urea;antiseborrhoeic agents, such as S-carboxymethylcysteine,S-benzylcysteamine and their derivatives, tioxolone; antibiotics such aserythromycin, neomycin or tetracyclins; agents which promote theregrowth of hair, such as minoxidil (2,4-diamino-6-piperidinopyrimidine3-oxide) and its derivatives, diazoxide and phenytoin; other steroid ornon-steroid anti-inflammatory agents; carotenoids and in particularβ-carotene; antipsoriasitic agents such as anthralin and itsderivatives; and phospholipase A₂ inhibitors.

These compositions can also contain taste-improvement agents,preservatives, stabilizers, moisture regulators, pH regulators, osmoticpressure-modifying agents, emulsifiers, UV-A and UV-B filters,antioxidants such as α-tocopherol, butylated hydroxyanisole or butylatedhydroxytoluene, local anaesthetics, buffers, and the like.

They can also be packaged in delayed-release or slow-release forms whichare known per se. Finally, they can be introduced into aqueous phases ofliposomes or niosomes.

The active substance according to the invention is present in thecompositions in proportions of between 0.01 and 10% by weight relativeto the total weight of the composition, and preferably between 0.01 and5%.

In therapeutic application, the treatment is determined by the doctorand can vary depending on the age, weight and response of the patient,as well as on the severity of the symptoms. The dosage is generallybetween 0.05 and 300 mg/kg/day, and preferably 0.5 to 100 mg/kg/day. Theperiod of treatment is variable depending on the severity of thesymptoms, and can extend for between 1 and 12 weeks in continuous ordiscontinuous fashion.

In cosmetic application, the compositions according to the invention aremainly used as products for use before exposure to sunlight and soothingproducts for use after exposure to sunlight, and for the treatment ofseborrheoic dermatitis and/or dermatitis involving acne.

The examples which follow are intended to illustrate the inventionwithout thereby being limitative in nature.

REFERENCE EXAMPLE Preparation of 5,8,11-eicoSatriynoic acid (a)Preparation of 1-chloro-2,5-tetradecadiyne

19.35 g of magnesium (0.79 gramme-atom) and then 750 cm³ of anhydroustetrahydrofuran (THF) are placed in a 2-liter round-bottomed flaskequipped with a stirrer and an argon inlet. 90.25 g of ethyl bromide(1.15 equivalent) are then introduced dropwise so as to maintain the THFrefluxing. When the addition is complete, this refluxing is maintaineduntil the magnesium has been completely converted. 100 g of 1-decyne(0.72 mol) are then added dropwise at this temperature in the course ofapproximately half an hour, and the mixture is maintained refluxing fora further hour and a half after the addition is complete. 5.20 g ofcuprous cyanide are then introduced and boiling is maintained for afurther hour. To the 1-decyne acetylide thereby formed, 250 g of1,4-dichloro-2-butyne, or 2.8 equivalents with respect to the decyne,are added at a temperature maintained at between 40° and 50° C. Boilingis maintained for 5 hours. The solvent is removed in a rotaryevaporator. The oily mass obtained is cooled and stirred in the presenceof 350 cm³ of water saturated with ammonium chloride, and then extracted3 times with ether. The ether phase is washed twice with water, driedover magnesium sulphate and then concentrated at normal pressure, andthe remaining ether is then removed under a pressure of 26.6×10² Pa. Thecrude 1-chloro-2,5-tetradecadiyne is distilled at a temperature ofbetween 118° C. and 125° C. under 2.6 Pa. In the final fractions atbetween 125° C. and 130° C. under 4 Pa, the remainder of the expectedproduct is distilled mixed with 1-bromo-2,5-tetradecadiyne, which formsduring the reaction by exchange of chlorine with bromine.

100 g of 1-chloro-2,5-tetradecadiyne containing approximately 3 to 5% of1-bromo-2,5-tetradecadiyne are obtained, determined by proton NMR, andthis used as it is in the final coupling stage.

(b) Preparation of 5-hexynoic acid

A solution of 115 g of 1-chloro-4-pentyne (1.12 mole) in 100 cm³ ofanhydrous dimethyl sulfoxide (DMSO) is introduced dropwise at atemperature of between 40° and 50° C. into a solution, placed under aninert atmosphere, of 60.4 g of sodium cyanide (1.23 mole) in 200 cm³ ofanhydrous DMSO. The reaction is exothermic and it is necessary to coolthe reaction mixture to maintain the temperature below 70° C. When theaddition is complete, the mixture is brought to between 60° and 70° C.for 5 hours and then left overnight at 20° C. It is then poured into 1.5liters of water. The mixture obtained is extracted four times with 200cm³ of ether. The ether phases are combined, then washed twice with 60cm³ of water and dried over sodium sulphate. The ether is distilled offunder reduced pressure. 101 g of 5-hexyne-1-nitrile are obtained. Thisis a yellow liquid which is used directly for the following stage. The ¹H NMR and IR spectra correspond to the expected structure.

200 g of the above nitrile (2.15 moles) are introduced into 2.5 litersof 2N potassium hydroxide. This mixture is stirred for two hours at 90°C. and then cooled to 0° C.; 5N hydrochloric acid is then added to themixture until the pH≃4. The mixture is extracted four times with 300 cm³of ether. The combined ether phases are washed twice with aqueousammonium chloride solution, then dried over magnesium sulphate andconcentrated under reduced pressure.

230 g of 5-hexynoic acid are obtained. This is a liquid at roomtemperature which crystallizes at 0° C. The NMR and IR spectracorrespond to the expected structure.

Elementary analysis: C₆ H₈ O₂

    ______________________________________                                                  C          H      O                                                 ______________________________________                                        Calculated  64.27        7.19   28.54                                         Found       64.32        7.21   28.41                                         ______________________________________                                    

(c) Preparation of 5,8,11-eicosatriynoic acid

In 200 cm³ of THF, 20.05 g of magnesium (0.835 gramme-atom) areconverted as above to ethyl magnesium bromide by adding 91 g of ethylbromide (0.835 mole). This ethyl magnesium bromide solution is added toa separately prepared solution, stirred at 0° C. under an inertatmosphere, containing 46.64 g of 5-hexynoic acid (0.417 mole) in 200cm³ of anhydrous THF.

When the addition is complete, 25 cm³ of hexamethylphosphoramide areadded, followed by 2.5 g of cuprous cyanide. The mixture therebyobtained is then brought for approximately one hour to a temperature of50° C. to ensure the complete conversion of the 5-hexynoic acid to thecorresponding acetylide in the form of magnesium carboxylate.

A solution containing 0.32 mole of 1-chlorotetradecadiyne in 100 cm³ ofTHF is added dropwise to this mixture at a temperature of between 40°and 50° C.

The reaction medium is brought to refluxing of the THF for 21 hours. Atthis stage, a further 1.3 g of cuprous cyanide is added and refluxing isstill maintained for a further 8 hours. The solvent is evaporated off.The viscous liquid obtained is acidified by adding 100 cm³ of 4Nsulphuric acid, followed by 100 cm³ of 2N sulphuric acid. Theheterogenous mixture obtained is extracted three times with 250 cm³ ofether. The ether phases are combined and washed twice using 150 cm³ ofsaturated aqueous ammonium chloride solution, decanted, dried oversodium sulphate and concentrated. The product obtained is taken up with100 cm³ of hexane and cooled to 0° C.

The crystals are drained, washed with ice-cold hexane and dried. 48 g of5,8,11-eicosatriynoic acid, of melting point 69°-70° C., are obtained.

The ¹ H NMR and IR spectra correspond to the expected structure.

PREPARATION EXAMPLE 1 Preparation of 2,3-dihydroxypropyl5,8,11-eicosatriynoate (a) Preparation of 5,8,11-eicosatriynoic acidchloride

4.1 g of phosphorus pentachloride are added slowly to a solution,stirred at 0° C., of 4 g of 5,8,11-eicosatriynoic acid in 50 cm³ ofanhydrous methylene chloride. After a quarter of an hour, the solutionis brought to reflux for two hours, after which time all the acid isconverted. The solvent and the phosphorus oxychloride are evaporated offunder reduced pressure. The acid chloride is thereby obtained and thiswill be used in the crude state for the subsequent reactions.

(b) Preparation of the ester of the alcohol2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane

The acid chloride obtained in state (a), solubilized in 30 cm³ ofanhydrous methylene chloride, is added to a mixture of 2.5 cm³ ofpyridine and 5 cm³ of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane in 50cm³ of methylene chloride, stirred at 0° C. under an inert atmosphere.The solution obtained is then left overnight at room temperature.

The reaction medium is washed with water, and the organic phase is driedover magnesium sulphate and then deposited on a chromatography column ofsilica gel. The expected ester is eluted with an ethyl acetate/hexane(1:9) mixture. After concentration of the elution phases, 2.7 g of esterare isolated in the form of a viscous liquid, the ¹ H NMR and IR spectraof which correspond to the expected structure.

(c) Release of the protective group from the 2,3-dihydroxypropyl group

A solution of 2 g of the above protected ester is stirred at roomtemperature in 30 cm³ of methanol in the presence of 2.2 g of Amberlite(sulphonic H⁺ resin) for three days.

It is ensured at this stage, using verification by thin layerchromatography, that the 1,3-dioxolane portion is converted to thecorresponding diol. The resin is then removed by filtration. Themethanol is evaporated off under reduced pressure, the liquid obtainedis solubilized in the minimum of methylene chloride and the solutionobtained deposited on a column of silica gel.

The ester is eluted with an ethyl acetate/hexane (75:25) mixture.

After concentration of the elution phases, 1.1 g of 2,3-dihydroxypropyl5,8,11-eicosatriynoate is obtained. The base peak (m/e: 374) in massspectrography corresponds well to the expected molar mass (M=374). The ¹H and ¹³ C 250-MHz NMR spectra show that this product containsapproximately 8% of its isomer, 1,3-dihydroxy-2-propyl5,8,11-eicosatriynoate.

PREPARATION EXAMPLE 2 Preparation ofN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide (1st synthesis route)

A solution of 1 g of eicosatriynoic acid chloride is added slowly to amixture, cooled to 0° C. under an inert atmosphere, of 0.36 g ofDiglycolamine and 0.23 cm³ of triethylamine in 20 cm³ of methylenechloride. The conversion of the acid chloride, followed by thin layerchromatography, is very rapid. When this is complete, the reactionmedium is poured into 100 cm³ of ice-cold water. The organic phase isdecanted. The aqueous phase is extracted again three times withmethylene chloride. The methylene chloride phases are combined, washedwith water saturated with ammonium chloride, then dried over magnesiumsulphate and concentrated. 0.6 g of amide is thereby isolated and thispurified by passage through a column of silica gel. The amide is elutedwith ethyl acetate. After evaporation of the eluent, 0.4 g ofN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide is obtained in theform of beige crystals, the melting point of which is 60° C.

The 250 MHz ¹³ C, infrared and mass spectra correspond to the expectedstructure.

PREPARATION EXAMPLE 3 Preparation ofN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide (2nd synthesis route)

A stirred solution of 15 g of 5,8,11-eicosatriynoic acid in 150 cm³ ofanhydrous dimethyl formamide is prepared under an atmosphere of argon,to which 10.5 g of carbonyldiimidazole are added at room temperature.The mixture is then brought for three hours to a temperature of between70° and 80° C. The mixture is cooled to 0° C. and 10.5 g ofDiglycolamine are then added drop-wise.

The mixture is stirred for a further quarter of an hour after theaddition is complete and then left overnight at room temperature andpoured onto 300 g of ice. The product precipitates. It is filtered off,washed with water and dried. The 18 g of amide are then recrystallizedin 150 cm³ of acetonitrile. 17 g ofN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide are obtained in theform of white crystals, the melting point of which is 63° C.

Elementary analysis: C₂₄ H₃₇ NO₃

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   74.37  9.62       3.61 12.38                                     Found        74.38  9.84       3.86 12.54                                     ______________________________________                                    

PREPARATION EXAMPLE 4 Preparation of N-ethyl-5,8,11-eicosatriynamide

A stirred mixture, under an atmosphere of argon, of 1 g of5,8,11-eicosatriynoic acid and 0.7 g of carbonyldiimidazole in 10 cm³ ofanhydrous DMF is brought for 3 hours to a temperature of 80° C.

A 33%-strength aqueous solution of N-ethylamine is then added at 0° C.in a single portion. After one hour, it is verified that the startingacid is completely converted to the corresponding amide. The reactionmixture is poured into 100 cm³ of ice-cold water. The precipitatedproduct is drained, washed with water and dried. 1.1 g of solid isobtained and this is recrystallized in 10 cm³ of ice-cold acetonitrile.

0.85 g of N-ethyl-5,8,11-eicosatriynamide is thereby isolated in theform of white crystals, the melting point of which is 68° C.

Elementary analysis: C₂₂ H₃₃ NO

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   80.68  10.15      4.27 4.88                                      Found        80.82  10.37      4.21 5.10                                      ______________________________________                                    

PREPARATION EXAMPLE 5 Preparation of pyrrolidino-5,8,11-eicosatriynamide

0.7 g of carbonyldiimidazole is added in a single portion to a solution,stirred under an atmosphere of argon, of 1 g of 5,8,11-eicosatriynoicacid in 10 cm³ of anhydrous DMF. The solution is then brought for threehours to 80° C. 0.5 g of pyrrolidine is then introduced at 0° C. Aftertwo hours, the reaction is complete.

The reaction mixture is then poured into 100 cm³ of ice-cold waterfollowed by extraction with methylene chloride. The organic phase iswashed with hydrochloric acid solution and then with water until the pHis neutral, dried over sodium sulphate and concentrated. 1.1 g ofpyrrolidino-5,8,11-eicosatriynamide is obtained in the form of a yellowliquid.

The IR and 250 MHz ¹ H NMR spectra are in agreement with the expectedstructure.

The elementary analysis corresponds to a hemihydrate: C₂₄ H₃₅ NO.1/2H₂O.

    ______________________________________                                                  C          H      N                                                 ______________________________________                                        Calculated  79.50        10.00  3.86                                          Found       79.22        9.38   4.00                                          ______________________________________                                    

PREPARATION EXAMPLE 6 Preparation ofN,N-bis(2-hydroxyethyl)-5,8,11-eicosatriynamide

The intermediate formed from 1 g of acid and 0.7 g of carbonyldiimidazole in 10 cm³ of anhydrous DMF is treated with 1 g ofdiethanolamine.

When all the acid is converted, the dimethylformamide is evaporated offunder reduced pressure. The liquid obtained is solubilized in methylenechloride and washed in acid medium, and the organic phase is dried oversodium sulphate and then stirred in the presence of 15 g of silica gel.This gel, to which the amide is bound, is filtered off. The amide isthen released by extracting the silica with ethyl acetate.

After evaporation of the solvent, 0.8 g ofN,N-bis(2-hydroxyethyl)-5,8,11-eicosatriynamide is obtained. At roomtemperature, it is a yellow liquid, the IR and 250 MHz ¹ H NMR spectraof which are in agreement with the expected structure.

PREPARATION EXAMPLE 7 Preparation ofN-(2-hydroxyethyl)-5,8,11-eicosatriynamide

A solution of 8 g of 5,8,11-eicosatriynoic acid and 5.62 g ofcarbonyldiimidazole in 40 cm³ of anhydrous DMF is brought to 80° C. for3 hours under an inert atmosphere. 3.25 g of ethanolamine are then addedat 0° C. After 2 hours, it is verified by thin layer chromatography thatthe starting acid is completely converted.

The reaction mixture is then concentrated by evaporation under vacuum,and then dissolved in 100 cm³ of methylene chloride. The solution iswashed with water and dried over sodium sulphate, and the methylenechloride removed by evaporation under vacuum. 9.1 g of solid areobtained. After recrystallization of the latter, 8 g ofN-(2-hydroxyethyl)-5,8,11-eicosatriynamide are isolated in the form ofwhite crystals, the melting point of which is 87° C.

The IR and 250 MHz ¹ H NMR spectra correspond to the expected structure.

Analysis: C₂₂ H₃₃ NO₂

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   76.92  9.68       4.01 9.31                                      Found        77.04  9.73       4.11 9.50                                      ______________________________________                                    

PREPARATION EXAMPLE 8 Preparation ofN-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide

In the same manner as in the above example, 8 g of 5,8,11-eicosatriynoicacid in 40 cm³ of anhydrous DMF are treated initially with 5.62 g ofcarbonyldiimidazole. 4.1 cm³ of 2,3-dihydroxypropylamine are then addedat 0° C. At the end of the reaction, the reaction mixture is poured intoice-cold water. The precipitated product is drained and dissolved in 300cm³ of methylene chloride. The solution is dried over sodium sulphateand then concentrated under reduced pressure. The solid obtained isdirectly recrystallized in acetonitrile. 9 g ofN-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide are thereby obtained inthe form of very pale beige crystals of melting point 87° C.

The IR and 250 MHz ¹ H NMR spectra are in agreement with the expectedstructure.

Elementary analysis: C₂₃ H₃₅ NO₃

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   73.95  9.44       3.75 12.85                                     Found        73.85  9.50       3.93 12.65                                     ______________________________________                                    

PREPARATION EXAMPLE 9 Preparation of4'-(2-hydroxyethyl)piperazino-5,8,11-eicosatriynamide

A mixture of 1 g of 5,8,11-eicosatriynoic acid and 0.7 g ofcarbonyldiimidazole (CDI) in 5 cm³ of anhydrous DMF is stirred under aninert atmosphere for 3 hours at a temperature between 70° and 80° C. Thesolution is then cooled to 0° C. and a solution of 0.8 g of1-(2-hydroxyethyl)piperazine in 5 cm³ of DMF is then added. Stirring ismaintained for 2 hours and the reaction medium is left overnight. Thesolvent is evaporated off under reduced pressure. The liquid obtained istaken up with methylene chloride and the solution is washed severaltimes with water, dried over sodium sulphate and concentrated underreduced pressure. 0.8 g of4'-(2-hydroxyethyl)piperazino-5,8,11-eicosatriynamide is obtained in theform of a yellow liquid.

The IR and 250 MHz ¹ H spectra correspond to the expected structure. Theelementary analysis corresponds to a partially hydrated product.

Elementary analysis: C₂₆ H₄₀ N₂ O₂.1/4H₂ O

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   74.86  9.78       6.71 8.63                                      Found        74.42  10.42      6.72 8.49                                      ______________________________________                                    

PREPARATION EXAMPLE 10 Preparation ofN-(para-hydroxyphenyl)-5,8,11-eicosatriynamide

In the same manner as in the above example, the intermediate formed from1 g of 5,8,11-eicosatriynoic acid and 0.7 g of CDI is treated with 0.727g of para-hydroxyaniline. The medium is then stirred for 24 hours atroom temperature. Water is then added gradually to the mixture until allthe product formed precipitates. It is drained and dried and thenrecrystallized in isopropyl ether. 0.85 g ofN-(para-hydroxyphenyl)-5,8,11-eicosatriynamide is obtained in the formof beige-white crystals of melting point 121° C.

The infrared and 250 MHz ¹ H NMR spectra are in agreement with theexpected structure.

Elementary analysis: C₂₆ H₃₃ NO₂

    ______________________________________                                                   C    H          N      O                                           ______________________________________                                        Calculated   79.75  8.49       3.57 8.17                                      Found        79.68  8.51       3.70 8.35                                      ______________________________________                                    

The examples which follow are intended to illustrate compositionsaccording to the invention.

EXAMPLE 1

The following composition is prepared:

    ______________________________________                                        2,3-Dihydroxypropyl 5,8,11-eicosatriynoate                                                              0.50   g                                            1-Propanol                50.00  g                                            Propylene glycol          10.00  g                                            Hydroxypropylcellulose    2.00   g                                            Water qs                  100    g                                            ______________________________________                                    

This composition takes the form of a gel with can be applied topically.Good results are also obtained by replacing 2,3-dihydroxypropyl5,8,11-eicosatriynoate in the composition byN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide.

EXAMPLE 2

The following composition is prepared:

    ______________________________________                                        N--2-Hydroxyethyl)-5,8,11-eicosatriynamide                                                               5.0    g                                           Micronized polyethylene    10.00  g                                           Isopropyl myristate qs     100    g                                           ______________________________________                                    

This composition takes the form of a hydrophobic ointment intended fortopical application. Good results are also obtained by replacingN-(2-hydroxyethyl)-5,8,11-eicosatriynamide in this ointment byN-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide or byN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide.

EXAMPLE 3

The following composition is prepared:

    ______________________________________                                        N--Ethyl-5,8,11-eicosatriynamide                                                                       1.00   g                                             Capric, caprylic and stearic acid                                             triglycerides            40.00  g                                             Capric and caprylic acid triglycerides                                                                 30.00  g                                             Vaseline                 20.00  g                                             Liquid paraffin qs       100    g                                             ______________________________________                                    

This composition takes the form of a hydrophobic ointment intended fortopical application.

It is possible to replace N-ethyl-5,8,11-eicosatriynamide in thisointment by pyrrolidino-5,8,11-eicosatriynamide.

EXAMPLE 4

The following composition is prepared:

    ______________________________________                                        4'-(2-Hydroxyethyl)piperazino-5,8,11-                                         eicosatriynamide          0.50   g                                            Cetyl alcohol             6.40   g                                            Cetyl alcohol oxyethylenated with 20 moles                                    of ethylene oxide         2.10   g                                            Glycerol monostearate     2.00   g                                            Capric and caprylic acid triglycerides                                                                  15.00  g                                            Propylene glycol          10.00  g                                            Water qs                  100    g                                            ______________________________________                                    

This composition takes the form of a cream intended for topicalapplication.

EXAMPLE 5

The following lotion is prepared:

    ______________________________________                                        2,3-Dihydroxypropyl 5,8,11-eicosatriynoate                                                              0.10   g                                            Ethanol                   50.00  g                                            Propylene glycol qs       100    g                                            ______________________________________                                    

This lotion is used for topical application.

The compositions of Examples 1 to 5 above are all manufactured andstored in an inert atmosphere and shielded from the light.

EXAMPLE 6

The following composition is prepared:

    ______________________________________                                        2,3-Dihydroxypropyl 5,8,11-eicosatriynoate                                                              0.01   g                                            Absolute ethanol          1.00   ml                                           Flavouring qs, preservative qs,                                               glycerole qs              5.00   ml                                           ______________________________________                                    

which is introduced into a 5-ml brown glass ampoule and intended for useorally in the form of a solution to be taken by mouth.

EXAMPLE 7

A 350-mg gelatin capsule is prepared containing a powder which has thefollowing composition:

    ______________________________________                                        N--(2-Hydroxyethyloxyethyl)-5,8,11-                                           eicosatriynamide         0.025  g                                             Microcrystalline cellulose                                                                             0.020  g                                             Maize starch             0.100  g                                             Colloidal silica         0.020  g                                             Magnesium stearate       0.185  g                                             ______________________________________                                    

We claim:
 1. A compound having the formula:

    C.sub.8 H.sub.17 --(C.tbd.C--CH.sub.2).sub.3 CH.sub.2 CH.sub.2 COR (I)

wherein R is (i) an amino group having the formula ##STR17## wherein R₁or R₂, which may be identical or different, denote a hydrogen atom or alinear or branched C₁ -C₈ lower alkyl radical, optionally interrupted byone or more hereto atoms chosen from oxygen, sulphur and nitrogen, saidlower alkyl radical being unsubstituted or substituted with one or morehydroxyl groups, R₁ and R₂ not being able to denote hydrogensimultaneously, or alternatively R₁ and R₂ form, together with thenitrogen atom, a heterocyclic system optionally containing oxygen,sulphur or nitrogen as an additional hetero atom, one of the radicals R₁and R₂ also being to denote, when the other is a hydrogen atom, an arylradical of formula (II): ##STR18## or alternatively a benzyl radical offormula (III): ##STR19## in which formulae R₃ and R₄, denote,independently of each other, a hydrogen atom, a C₁ -C₄ alkyl radical, ahydroxyl group, a halogen atom or a carboxyl or trifluoromethyl group or(ii) a glucosamine, and the isomers and salts thereof which arepharmaceutically and cosmetically acceptable.
 2. Compound according toclaim 1 whereinR denotes an amino group of formula ##STR20## at leastone of the groups R₁ and R₂ denotes a C₁ -C₄ lower alkyl radical, or alower alkyl radical interrupted by an oxygen atom and/or substitutedwith one or more hydroxyl groups.
 3. Compound according to claim 1,wherein R represents ##STR21## and wherein at least one of the groups R₁and R₂ denotes a C₁ -C₈ alkyl radical optionally interrupted by one ormore oxygen atoms and substituted with one or more hydroxyl groups; oralternatively R₁ and R₂ form, with the nitrogen atom, a heterocyclicsystem optionally containing one or more oxygen, sulphur or nitrogenatoms as additional hetero atoms.
 4. Compound according to claim 3,whereinat least one of the groups R₁ and R₂ are selected from the groupconsisting of: CH₂ CH₂ OCH₂ CH₂ OH, CH₂ CH₂ OH, CH₂ CHOHCH₃, and CH₂CHOHCH₂ OH.
 5. Compound according to claim 3, which is theN-(2-hydroxyethyloxyethyl)-5,8,11-eicosatriynamide.
 6. A pharmaceuticalcomposition for oral or local administration, comprising a carrier or adiluent which is pharmaceutically acceptable, and a therapeuticallyeffective amount of at least one compound as defined in claim
 1. 7. Apharmaceutical composition for topical administration, in the form of acream, tincture, ointment, salve, powder, patch, impregnated pad,solution, gel, lotion, spray or suspension, comprising a therapeuticallyeffective amount of at least one compound as defined in claim
 1. 8. Apharmaceutical composition in a form for parenteral administrationintravenously, intramuscularly, subcutaneously or intradermally,comprising a therapeutically effective amount of a compound as definedin claim 1 in a pharmaceutically acceptable diluent.
 9. A pharmaceuticalcomposition for enteral administration in the form of a tablet, gelatincapsule, dragee, syrup, suspension, solution, powder, granule oremulsion, comprising a therapeutically effective amount of a compound asdefined in claim
 1. 10. A pharmaceutical composition according to claim7 comprising a therapeutically effective amount of the active compoundof formula (I) in proportions of 0.1 to 10% by weight relative to thetotal weight of the composition.
 11. A cosmetic composition, comprisinga therapeutically effective amount of at least one compound as definedin claim 1 in a proportion of between 0.1 and 10%.
 12. The compound ofclaim 1 wherein R₁ and R₂ form a pyrrolidine, morpholine, piperazine or4-(2-hydroxyethyl) piperazine heterocyclic system.
 13. The compound ofclaim 1 selected from the group consistingofN-ethyl-5,8,11-eicosatriynamide, pyrrolidino-5,8,11-eicosatriynamide,N,N-bis(2-hydroxyethyl)-5,8,11-eicosatriynamide,N-(2-hydroxyethyl)-5,8,11-eicosatriynamide,N-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide,N-(para-hydroxyphenyl)-5,8,11-eicosatriynamide, and ' -(2-hydroxyethyl)piperazino-5,8,11-eicosatriynamide.